Copyright
©The Author(s) 2023.
World J Clin Oncol. Jul 24, 2023; 14(7): 230-246
Published online Jul 24, 2023. doi: 10.5306/wjco.v14.i7.230
Published online Jul 24, 2023. doi: 10.5306/wjco.v14.i7.230
Table 1 Summary of various inflammatory and fibrotic conditions and relevant malignancies
Disease | Associated cancer | Mechanism | Risk ratio | Possible therapeutic targets |
Inflammatory bowel disease | Colorectal cancer | Increased pro-inflammatory cytokines (TNF-α, IL-6 and TGF-β)[24,30,34]; Increased signalling of pro-tumorigenic molecular pathways, apoptosis resistance, fibrogenesis (NF-ĸB and Wnt/β-catenin)[9,27,30,34] | Ulcerative colitis – 4.8-fold increase[13]; Crohn’s disease – 2-3-fold increase[17] | Thiopurines[173] and anti-inflammatory such as mesalazine[174] and NSAID[149] |
Chronic pancreatitis | Pancreatic ductal adenocarcinoma | Increased cytokines (TNF-α and TGF-β), growth factors (VEGF, PDGF)[38]; Fibroblast and pancreatic epithelial cell proliferation[40]; Activation of pancreatic stellate cells[39,40]; Increased ECM protein (collagen 1 and 4, laminin, fibronectin) and hyaluronic acid deposition[38] | 20-fold increase[35] | PEGylated Recombinant Human Hyaluronidase[45,46]; NSAID[149] |
Idiopathic pulmonary fibrosis | Lung cancer | Cellular morphological abnormalities (metaplasia, dysplasia) in fibrotic areas[59]; Reduced immune expression (monocytes, lymphocytes, macrophages) in fibrotic areas[50]; Mutations in tumour-suppressor genes[54]; Upregulated gene expression of ECM components such as collagen and MMP (MMP9 and 11)[57] | 3.5-7.3 fold increase[51] | Anti-fibrotic drugs (pirfenidone and nindetanib)[175] |
Pneumoconiosis | Lung cancer | Silicosis: Chronic increased release of pro-inflammatory cytokines (IL-12, IL-23 and TNFα) results in DNA damage[66]; Immunosuppression through increased expression of inhibitory immune markers (PD-1, LAG3, FOXP30)[70]. Asbestosis: Increased inflammation (IL-1β, TGF-β and PDGF) and fibrosis through expression of NLRP3[70]; Increased ROS and RNS[64,68]; Increased expression of proliferation signalling pathways (EGFR-ERK)[73] | Silicosis – 3-fold increase[15]; Asbestosis – 1.5-6.8-fold increase[65,65] | Anti-fibrotic drugs (pirfenidone and nindetanib)[152] |
TB | Lung cancer | Upregulation of anti-apoptotic protein expression via inflammatory cytokines (TNF-α and IL-6)[59,76,78] | Pneumonia – 1.4-fold increase[14]; TB – 1.9-fold increase[14] | NSAID[176] |
Liver cirrhosis | Hepato-cellular carcinoma | Cellular proliferation, telomere shortening via inflammatory cytokines (TGF-β, TNF-α and interleukins)[83,84]; Genomic instability (p53, Ras, mTOR, Wnt signalling pathways)[11,84]; Reduced expression of CD4+ and CD8+ cytotoxic T cell[85]; Increased regulatory T-cell response[86]; Activation of hepatic stellate cells increase myofibroblast and ECM production[11,87]; Hypoxia in fibrosis leads to genotoxicity (ROS, RNO) and angiogenesis (VEGF)[92] | Hepatitis B related – 1.17-fold increase[81]; Hepatitis C related - 1.15-fold increase[81]; NAFLD-related – 1.6-23.7-fold increase[161] | LOX/LOXL2 inhibitors[161,162]; NSAID, Pentoxifylline[177,178] |
Primary biliary cholangitis | Cholangiocarcinoma | Increased proliferative signalling via inflammatory cytokines (IL-1β, IL-6 and HGF)[96-98]; IL-6 activates p38-MAPK, increases DNA methyltransferase (DNMT) Mcl-1 and telomerase expression[96]; DNA damage (BRAF, K-ras, cyclin d-1, c-myc, COX-2 and p53) due to dysregulated NO production[98]; Fibroblast proliferation and ECM production (collagen type 1 and 3)[103] | 9-fold increase[94] | Natural anti-inflammatory products (Curcumin)[102] |
GERD and Barrett’s oesophagus | Oesophageal cancer | Increased inflammatory cell recruitment (macrophages T, B, dendritic cells)[107]; Inflammatory cytokine release (TNF-α, IL-6, IL-1β, IL-8) activates pro tumorigenic signalling pathways (NF-Κb, STAT-3, HIF-1a)[107,108]; Reduced immune response due to immunosuppressive cytokines (IL-10)[112]; Oxidative stress (ROS and RNS) induce mutagenesis of oncogenes and tumor suppressor genes[110] | 30-125-fold increase[106] | NSAID[149] |
OSF | Oral squamous cell carcinoma | Increased inflammatory cell recruitment[118]; Oxidative stress induces p53 mutation, decreased DMNT and increased HSP70 and MDM2-P2 promoter[120,122]; Increased prostaglandins, cytokines and growth factors (IL-6, TNF-α, PDGF and TGF-β)[118,119]; Fibrogenesis via IL-6 and TGF-β leads to increased ECM protein production (collagen, fibonectin) and inhibit ECM breakdown (PAI-1, TIMP)[124,125]; OSF-associated fibroblast promote dysplastic keratinocyte proliferation via GRO-α release and EGFR/ERK activation[128] | 19-fold increase[114] | Anti-oxidants, steroids and hyaluronidase[178] |
Physiological breast stromal density, breast conditions – chronic mastitis, sclerosing adenosis | Breast cancer | Mammographically dense breast have higher ECM proportion (collagen, immune cells)[131,133]; Mammographically dense breast have higher proportion of glandular epithelial components and lower proportion of adipocytes[132-134] | Physiological higher MBD: 4-6-fold increase[130]; Chronic mastitis: 3-fold increase[137]; Sclerosing adenosis: 2-fold increase[138] | Anti-estrogens (tamoxifen, raloxifene, exemestane and anastrozole)[154-157]; NSAID[149]; LOX-like inhibitors[159,160,163] |
- Citation: Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14(7): 230-246
- URL: https://www.wjgnet.com/2218-4333/full/v14/i7/230.htm
- DOI: https://dx.doi.org/10.5306/wjco.v14.i7.230